Certain pharmaceutical drugs are known to suppress respiration. Of those pharmaceutical drugs, opioid receptor agonists (also described herein as either “opioids” or “narcotics”) are the most well-known.
Most often, opioids are currently used to treat pain. Opioids are potent analgesics and they are prescribed for patients in pain who need powerful painkillers. Acute pain, (for example, pain in duration of less than three months), is treated most often with short acting immediate release opioid medications, while chronic pain, (for example, pain in duration of greater than three months), is treated often with long acting or extended release formulations of opioid medications.
Chronic nonmalignant pain is a silent epidemic in the U.S. that affects approximately 116 million Americans. Patients who take opioids for an extended period, can develop a tolerance and require higher and higher doses of the drugs, increasing the risk of overdose and other problems. It is also the most common reason patients seek medical care, resulting in $635 billion annually in both medical costs and decreased work productivity. Although the physiology of chronic pain continues to be poorly understood, it has been identified as a disorder associated with many psychosocial conditions, including lack of appetite, depression, and sleep disturbances.
Opioids have well-known pharmacodynamic profiles associated with a significant number of side effects and complications. Common side effects of opioid administration include sedation, dizziness, nausea, vomiting, and constipation. Less common side effects may include delayed gastric emptying, hyperalgesia, immunologic and hormonal dysfunction, infertility, muscle rigidity, myoclonus, physical dependence, tolerance, respiratory depression, respiratory arrest and death. Painkiller deaths quadrupled between 1999 and 2011, mirroring a sharp rise in the number of prescriptions for such drugs. In 2009, overdoses involving painkillers pushed drug fatalities past traffic accidents as a cause of death. In 2011 the U.S. Centers for Disease Control and Prevention declared prescription opioid abuse an epidemic.
Well-known complications of opioids include the phenomenon of both physical and psychological dependence and addiction, which can in turn lead to opioid misuse, abuse and diversion. More than 70% of the illegal users obtain opioids by stealing them during pharmacy robberies, purchasing them illegally on the black market, or receiving them from family or friends. These individuals seek to achieve a “high” from prescription medications by taking an excess number of pills orally or by crushing the pills, followed by snorting, smoking, or injecting the new altered formulation. The misuse or abuse of prescription opioid medications is a growing problem, with abuse rates having quadrupled in the decade from 1990 to 2000. The deaths associated with abuse and misuse of prescription pain drugs have also quadrupled between 1999 and 2011. Frequently death associated with the overdose of opioids occurs within an hour of the administration of the opioid due to respiratory suppression.
Because the availability of opioids has increased, there are now more deaths and overdoses from prescription opioids than deaths from heroin overdoses. A study published in the November 2014 issue of the journal Pain found an increased risk of death associated in patients with chronic pain prescribed opioids for long-term use while a somewhat lower risk was associated with short-term use.
The increased availability of opioids was partially brought about by The Joint Commission On Accreditation of Healthcare Organizations (JCAHO) standards from 2000 that demands pain be addressed by healthcare providers as the fifth vital sign. The evaluation of pain was thus made equivalent to the evaluation of a patient's vital signs including the heartbeat, blood pressure, respiratory rate, and temperature. A 2012 study showed that physicians played an important role in prescription drug overdoses as they attempted to comply with Federal mandates, avoid malpractice claims, avoid decreased patient satisfaction scores (as patients began demanding more prescriptions for opioid pain medications), and avoid decreased reimbursement. The same study found that of 3,733 fatalities associated with prescription opioid drugs, the drugs that caused or contributed to nearly half of the deaths were prescribed to patients by physicians. This public health issue confounds the clinical utility of opioids. The extent of their efficacy in the treatment of pain when utilized on a chronic basis has not been definitively proven and has made long-term treatment of non-cancer pain with opioids controversial. Coupled with the abuse and addiction potential, clinical safety concerns and side effect profile, proper physician prescribing of opioids may be prevented, and result in inadequate pain management.
Though the bulk of the current research is focused on abuse deterrence, addiction avoidance and patient safety, prescription drug are still abused, overdoses occur and death rates continue to rise. It is apparent that this approach is not successful in preventing patient deaths. The abuse deterrent developments have either been too difficult to manufacture or fail in clinical use. “Mu receptor Modulation” has not worked. A different approach must to be tried to save patient lives. Presently, as abuse deterrence technologies are developed, narcotic abusers and addicts quickly discover innovative methods to achieve their goal of reaching a euphoric “high”. They crush drugs, intravenously inject drugs, snort drugs, extract drugs with alcohol or combine multiple drugs to defeat pharmaceutical abuse deterrence technology as they are developed. It is a cycle that has led to many deaths. The CDC determined that abuse of prescription opioid drugs is an epidemic because it has led to a quadrupling of death rates in recent years. Rethinking of the method in which pain is treated with opioids must be done. The current trend to use multimodal pain therapy, which utilizes non-narcotics in synergy to treat pain is a step in the right direction. Unfortunately, in clinical practice this has been implemented by only about 30 percent of physicians in the country. Rethinking of the method in which opioids are used to treat pain must also be done. There is an epidemic of prescription drug abuse and it is getting worse despite efforts to solve it. More opioid pain medications are prescribed today than ever before because of Federal JCAHO regulations mandating the treatment of pain. The pharmaceutical industry's attempts to develop effective abuse deterrent solutions have largely been unsuccessful. And even though the Federal government regulations including REMS (Risk Evaluation and Mitigation Strategies), CURES (Controlled Substance Review Evaluation System), and ETASU (Elements to Assure Safe Use) regulations to restrict prescribing practices for opioid use have been implemented, deaths from overdose still occurs.
Progressive and ultimately life-threatening respiratory events may go unrecognized until significant morbidity or mortality occurs. Drug-induced respiratory depression (DIRD) is a common problem with opioid use. It is not always possible to predict the timing or severity of DIRD due to the number of contributing factors. To illustrate, among postoperative patients receiving opioids, the incidence of clinically significant respiratory depression (respiratory acidosis and hypoxemia) requiring intervention occurs in approximately 2% of the surgical population. Unfortunately, it is not always possible to predict the timing or severity of these events due to the number of contributing factors, including age, sex, body-mass index, presence of co-morbidities, and concomitant medications administered. On the other hand, some risk factors are very strong predictors of respiratory complications post-operatively. For example, in bariatric patients the incidence of deleterious respiratory events post-operatively may be as high as 100%. Typically, in the immediate post-operative period and while in the post-anesthesia care unit, a patient's ventilatory performance is monitored intensively and respiratory depression can be treated early with interventions such as verbal stimulation, oxygen therapy, and positive airway pressure (i.e., CPAP). Occasionally, profound respiratory depression requires reversal by administering a selective antagonist of naloxone or flumazenil, and/or decreasing subsequent doses of the depressant agent. Although this approach may improve respiratory function, sedation and/or analgesia will be sub-optimal. If a safe and effective respiratory stimulant drug were available to support breathing post-operatively it is likely that pain control in some patients would improve because analgesia could be used as the endpoint for titration of an opioid rather than the magnitude of respiratory depression it elicits. A safe and effective respiratory stimulant could improve patient care by avoiding the use of opioid reversal agents (e.g., naloxone, which reverses analgesia as well as respiratory depression) thereby permitting better pain management by enabling the use of higher doses of analgesics. Thus, there is a need for a respiratory stimulant beyond the post-anesthesia care unit.
A novel new pain medication could break the cycle whereby addicts who continue to abuse opioids do not die, and the use of opioids becomes a safer option.
In view of the consequences of increased opioid prescription and/or administration there is an apparent unmet need for a safe method of treating pain, which adequately addresses the pain levels of acute and/or chronic pain sufferers yet also decreases the risk of overdose by pain medications. Further, in view of the consequences of patient tolerance to increased levels of analgesics, there is a need to safely administer high doses of active agents to the patients, while avoiding the side effects which lead to death, such as respiratory suppression.